Enema and enterically-coated oral dosage forms of azathioprine

ABSTRACT

This invention relates to enema and enterically-coated dosage forms having an amount of azathioprine effective to prevent colorectal adenomas without dose-limiting systemic toxicity.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 09/310,505, filed May 12, 1999, now U.S. Pat. No. 6,166,024,which is a continuation-in-part of U.S. patent application Ser. No.08/905,490, filed Aug. 1, 1997 (now U.S. Pat. No. 5,905,081, issued May18, 1999), which is a divisional of U.S. patent application Ser. No.08/413,505, filed Mar. 30, 1995 (now U.S. Pat. No. 5,691,343, issuedNov. 25, 1997).

BACKGROUND OF THE INVENTION

Inflammatory bowel disorders or diseases (IBD) encompass a spectrum ofoverlapping clinical diseases that appear to lack a common etiology.IBD, however, are characterized by chronic inflammation at various sitesin the gastrointestinal (GI) tract. Illustrative IBD are regionalenteritis (or Crohn's disease), idiopathic ulcerative colitis,idiopathic proctocolitis, and infectious colitis. Most hypothesesregarding the pathogenesis of IBD concern the implication ofimmunologic, infectious, and dietary factors.

Colorectal cancer is the most common visceral cancer in the UnitedStates. The colorectal cancer progresses through clinically recognizablestages from normal mucosa through enlarging and increasingly dyplasticpolyps to carcinoma. The precursor relationship of colorectaladenomatous polyps to carcinoma and the high prevalence of adenomas makethem an attractive target in chemoprevention trials. Furthermore,endoscopic or surgical removal of polyps does not change thepathogenetic milieu responsible for their growth and development. Therecurrence rate for colorectal adenomas ranges from 20-60% by two years.Patients who have undergone surgical resection of a primary colorectalcancer have also been shown to be at high risk of developingmetachronous adenomas. Chemoprevention by pharmacologic interventionremains to be established in clinical practice, and there is acontinuing need to develop new chemopreventive treatments for colorectaladenomas. 6-mercaptopurine (6MP) and its prodrug azathioprine (AZA) havebeen used in the treatment of inflammatory bowel disease (IBD) for over25 years. Multiple controlled trials and a recent meta-analysis supportthe efficacy of 6MP and AZA in Crohn's disease. See, J. M. T. Willoughbyet al., Lancet, ii 944 (1971); J. L. Rosenberg et al., Dig. Dis., 20,721 (1975). Several controlled trials support the use of AZA inulcerative colitis, the most recent by Hawthorne and colleagues, inBrit. Med. J., 305, 20 (1992). Both azathioprine and 6-mercaptopurinehave also demonstrated anti-tumor activity against a wide variety oftransplantable rodent tumors and against hematologic malignancies inman. However, use of 6MP and AZA has been limited by concerns abouttheir toxicities. Dose-related leukopenia is seen in 2-5% of patientstreated long-term with 6MP or AZA for IBD. See, for example, D. H.Present et al., Am. Int. Med., 111, 641 (1989); W. R. Connell et al.,Gut, 34, 1081 (1993).

Therefore, a need exits for effective, nontoxic therapies for IBD.Furthermore, there is also a need for new chemopreventative treatmentsfor colorectal adenomas.

SUMMARY OF THE INVENTION

The present invention provides new therapeutic methods of treatinginflammatory bowel disease (IBD) and colorectal adenomas comprisingtopically administering to the colon of a patient in need of suchtreatment, an amount of azathioprine (AZA) effective to relieve thesymptoms of said IBD or to prevent colorectal adenomas, either prior toor following endoscopic or surgical removal. Preferably the azathioprineis administered orally, by means of an enteric-coated unit dosage formthat selectively releases AZA in the terminal ileum and/or colon of thepatient. The AZA can also be effectively administered to the colon byrectal administration of an enema formulation comprising AZA. Due topoor absorption of AZA in the bloodstream from the colon, relativelyhigh doses of AZA can be administered to the afflicted tissue, i.e., inthe case of Crohn's disease, ulcerative colitis, or colorectal adenomaswithout inducing systemic toxicities such as leukopenia, Therefore,effective AZA doses of from about 150-1000 mg can be delivered 1-4 timesdaily to adult patients (150 mg 1×day-1000 mg 4×day) without unduetoxicities (about 2-20 mg/kg AZA doses are administered).

As used herein the term “azathioprine” includes the pharmaceuticallyacceptable salts thereof, as well as functionally equivalent analysis,derivatives, and metabolites, such as 6-MP and thioguanine. For example,see U.S. Pat. No. 3,056,785, and W. P. Wilson et al., Anal. Profiles ofDrug Substances, 10, 29-53 (1981).

DETAILED DESCRIPTION OF THE INVENTION

Colonic administration of drugs has been used to reduce the toxicityassociated with oral or IV corticosteroids and oral 5-aminosalicyclatein patients with IBD. This decreased toxicity is believed to be due toreduced systemic bioavailability. Several types of colonic drug deliverysystems are currently available, including enemas (L. R. Sutherland etal., Med. Clin. North Amer., 74, 119 (1990)); rectal foams (Drug. Ther.Bull., 29, 66 (1991)); and delayed release oral formulations in the formof Eudragit-coated capsules which dissolve at pH 7 in the terminal ileum(K. W. Schroeder et al., New Engl. J. Med., 317, 1625 (1987)).

The effective amount of azathioprine (AZA) can be topically administeredto the colon of the patient by oral ingestion of a unit dosage formcomprising an effective amount of AZA which is enterically coated so asto be released from the unit dosage form in the lower intestinal tract,e.g., in the terminal portion of the ileum and in the colon of thepatient. Microparticles of AZA may be individually coated and deliveredas a suspension in a liquid vehicle, may be encapsulated as a powder ormay be compressed into a pill or tablet and swallowed. Alternatively,the azathioprine may be combined with adjuvants employed in solid unitdosage forms, such as fillers and binders, compressed into shaped, soliddosage forms such as pills or tablets, and the pills or tablets treatedso as to apply an enteric coating of suitable thickness thereto.

Enteric coatings are those which remain intact in the stomach, but willdissolve and release the contents of the dosage form once it reaches thesmall intestine. The purpose of an enteric coating is to delay therelease of the AZA until it reached the target site of action in thecolon. Since the AZA topically-administered to the colonic tissue inthis fashion is only about 10% absorbed into the bloodstream, thesystemic side-effects of AZA can be avoided or minimized.

Thus, a useful enteric coating is one that remains undissociated in thelow pH environment of the stomach, but readily ionizes when the pH risesto about 4 or 5. The most effective enteric polymers are polyacidshaving a pHa of 3 to 5.

The most extensively use polymer is cellulose acetate phthalate (CAP)which is capable of functioning effectively as an enteric coating.However, a pH greater than 6 usually is required for solubility and thusa delay in drug release may ensue. Another useful polymer is polyvinylacetate phthalate (PVAP) which is less permeable to moisture and gastricfluid, more stable to hydrolysis and able to ionize at a lower pH,resulting in earlier release of actives in the duodenum.

A more recently available polymer is hydroxypropyl methylcellulosephthalate. This has similar stability to PVAP and dissociates in thesame pH range. A further example of currently used polymers are thosebased on methacrylic acid, e.g., methacrylic acid ester copolymers withacidic ionizable groups, such as Eudragit S-100 (methacrylic acidcopolymer). Various systems are available that allow each of theseenteric polymers to be applied as aqueous dispersions, thus facilitatingthe use of aqueous film-coating technology for the enteric coating ofpharmaceutical dosage forms.

Another preferred dosage form in the topical administration of AZA tothe colon is an enema formulation, which is rectally administered to thelower colon. Useful formulations comprise an effective amount of AZAdissolved or dispersed in a suitable flowable carrier vehicle, such aswater, alcohol or an aqueous-alcoholic fluid. The carrier vehicle ispreferably thickened with natural or synthetic thickness such as gums,acrylates or modified celluloses. The formulation can also comprise aneffective amount of a lubricant such as a natural or synthetic fat oroil, i.e., a tris-fatty acid glycerate or lecithin. Nontoxic nonionicsurfactants can also be included as wetting agents and dispersants. Unitdosages of enema formulations can be administered from prefilled bags orsyringes. The carrier vehicle may also comprise an effective amount of afoaming agent such as n-butane, propane or i-butane. Such formulationscan be delivered from a pressurized container, so that the vehicle isdelivered to the colon as a foam, which inhibits its release from thetarget site.

Generally, once colorectal polyps are identified, they areendoscopically or surgically removed. Chemoprevention follows removal.However, patients at high risk to develop colorectal polyps couldbenefit from chemoprevention prior to identification of the adenomas.Such patients may have a strong family history of colorectal polyps orcancer, presence of long-standing extensive ulcerative colitis, orfamily cancer syndromes such as familial adenomatous polyposis or LynchSyndrome. In these situations, delayed release oral AZA would result ina decreased frequency of the development of colorectal polyps.

The invention will be further described by reference to the followingdetailed examples.

EXAMPLE 1 Preparation of Hydrophilic Rectal AZA Foam

To 948.4 g of purified distilled water containing 1.4 g and 0.14 g ofmethyl- and propylparaben respectively as preservatives; 2.0 g KELTROLTF (xanthan gum, suspending agent) were added and dispersed. Then 2.0 gof SOYA LECITHIN emulsifying agent (unbleached) were also dispersed aswell as 5.0 g of carbomer (CARBOPOL 974 P NF). The carbomer was thenneutralized with 2 g of sodium hydroxide dissolved in 20 ml of purifiedwater (pH 7.10). Then 10.0 g of POLYSORBATE 80 (surfactant) were addedto the mixture along with 0.250 g CITRAL (perfume) and the twocomponents were dispersed. Finally, 2.366 g of AZA were added and alsodispersed. The theoretical content of Azathioprine in this formulationwas 50 mg/21 g of mixture. Viscosity of the concentrate measured inBrookfield-viscometer DV-II at 20° C. and 12 rpm using spindle 64 was:29, 700 CPS.

The concentrate was then mixed with n-butane (foaming agent) usingstandard equipment for the preparation of aerosols. The n-butane contentin the aerosol mixture was 2.5%. The mixture was then filled intocanisters of the Sepro bag-in-can type (containing a collapsiblelamipack bag mounted on a valve and fitted into a monoblock aluminumcan: the propellant was nitrogen present in the monoblock and thusseparated from the aerosol concentrate of the bag). The can was equippedwith a nozzle and a canula. The delivered amount of concentrate percanister was 21±1 g leading to 200-220 ml of foam at 37° C.

EXAMPLE 2 Hvdrophobic Rectal AZA Foam

To 948.45 g of purified distilled water containing 1.43 g and 0.14 g ofmethyl- and propylparaben respectively: 2.0 g of KELTROL TF (xanthangum, suspending agent); 2.0 g of unbleached SOYA LECITHIN (emulsifyingagent); 5.0 g of CARBOPOL 974 P NF (carbomer) were added and dispersedwith a SILVERSON homogenizer. The carbomer was neutralized with 2.0 g ofsodium hydroxide dissolved in 20 ml of purified distilled water, pH7.05.

Then 47.40 g WITEPSOL H 15 (Hard Fat NF) an hydrophobing agent wereadded and very efficiently dispersed in the mixture using a SILVERSONhomogenizer. A creamy concentrate having an hydrophobic feel wasobtained.

10.50 g of POLYSORBATE 80 (surfactant) and 0.25 g CITRAL (perfume) wereadded and also dispersed with the homogenizer. To stabilize thisemulsion and particularly the corresponding foam, 20.80 g of POLAWAX NF(as non-ionic emulsifying wax) were added and dispersed in the mixture.Finally 1.93 g of AZA was added and also dispersed. The theoreticalcontent of the Azathioprine in the formulation was 50 mg in 27.5 g ofmixture. Viscosity of the concentrate measured as for AZA-1:41,000 CPS.The concentrate was then mixed with n-butane (foaming agent) as forsample AZA-1, n-butane content: 2.5%. The mixture was then filled intocanisters of the Sepro bag-in-can type. The delivered amount ofconcentrate per canister was 27.5 g±1 g leading to 205-220 ml of foam at37° C. The hydrophobic foam had a lower expansion ratio than thehydrophilic foam.

EXAMPLE 3 Preparation of AZA Enteric-Coated Capsules

1 IMURAN tablet (50 mg Azathioprine tablet containing 50 mg AZA(Burroughs Wellcome Co.) was crushed in a mortar; and the powder wasfilled in a size 2 hard gelatin capsules. The capsules were closedmanually. Each capsule was weighed individually (IPC)

The capsules were banded on a laboratory type banding machine with a 50wt % solution of gelatin in water (1% polysorbate 80). The capsule wasfinally coated in a laboratory coating machine by the spraying with anaqueous solution of Eudragit S-100 (1N NH₄OH). The finished capsules (12wt-% Eudragit) were resistant to artificial gastric juice (pH 1.2) for 2hours, but disintegrated in artificial gut juice (pH 7.2) in no morethan 60 minutes.

EXAMPLE 4 Topical Colonic Administration of AZA

A. Subjects: Twenty-four healthy human volunteers were recruited andscreening physical exam and laboratory studies (complete blood count,chemistry panel, and urinalysis) were performed. Prior to study entry,the erythrocyte thiopurine methyltransferase (TPMT) activity wasdetermined in all patients and subjects with homozygous or heterozygouslow TPMT activity were excluded from the study because of prior reportsof severe neutropenia associated with AZA or 6MP use in this population.Subjects were screened for medical conditions or a surgical historywhich could impact AZA absorption or its metabolism. Demographics ofsubject group are summarized in Table 1. There were no statisticallysignificant differences between the groups for the parameters indicated.

TABLE 1 Age Weight TPMT level Group Number (yr) (kg) (Units/ml RBC) Oral6 27.7 ± 7.5  80.3 ± 20.0 21.9 ± 2.3 DRO 6 36.7 ± 18.5 87.9 ± 44.0 21.2± 2.6 HBF 6 29.2 ± 5.8  83.7 ± 11.6 23.5 ± 4.0 HPF 6 33.2 ± 8.2  71.7 ±10.0 19.5 ± 1.8 *mean ± SD

B. Study Design: The 24 healthy human subjects were randomly assigned toreceive 50 mg of one of four AZA dosage formulations (each n=6): oral:delayed-release oral (DRO); hydrophobic rectal foam (HBF); andhydrophilic rectal foam (HPF). All subjects also received a 50 mg doesof intravenous (IV) AZA. The two doses of AZA were separated by at least3 weeks and the order of dosing (IV vs. non-IV) was randomly determined.Subjects fasted after midnight the night prior to the study. If rectalfoam were to be administered, subjects were given a Fleet's enema ifthey had not had a bowel movement the morning of the study.

The intravenous dose (see below) was administered as an infusion dilutedin 20 ml of normal saline and delivered over 5 minutes. The oralpreparations were administered with a sip of water. Rectal formulationswere administered by a nurse. Subjects remained fasting for three hoursfollowing dose administration. A time zero blood sample was obtainedprior to the study. After dose administration or after initiation of theIV infusion, blood samples were drawn in 7 ml EDTA (K₃)-containingvacuum tubes (Sherwood Medical, St. Louis, Mo.) at the following timeintervals: 5, 10, 15, 30 minutes and 1, 1.5, 2, 3, 4, 5, 6, and 8 hours.

The AZA pharmacokinetics were studied by determining 6MP bioavailabilityrather than AZA bioavailability because of the availability of reliabletechniques for measuring plasma 6MP levels. In addition, 6MP is the morebiologically relevant molecule, as AZA functions as a prodrug for 6MP.Following absorption, AZA is quickly converted to 6MP via non-enzymaticattack on the bond between the imidazole ring and the 6MP molecule bysulfhydril-containing compounds such as glutathione. 6MP is thenmetabolized to compounds with immunomodulatory activity, the6-thioguanine nucleotides (6TGN).

C. Determination of 6MP concentration in Plasma: Immediately aftercollection, blood samples were placed in an ice-water slurry. Within 30minutes the blood sample was centrifuged for 10 minutes at 1000 g, 4° C.Plasma was then transferred to plastic cryotubes (Nunc Inc., Naperville,Ill.) and stored at −70° C. until analysis. 6MP concentrations weredetermined by HPLC using the technique of Zimm (20) with modifications.Solid phase extraction columns (C18 Sep-Paks, Waters, Inc., Millford,Mass.) were sequentially pre-rinsed with 2.5 ml of methanol and 5 ml of0.2% acetic acid. One ml of plasma was loaded onto the Sep-Pak followingaddition of 0.04 ml of saturated EDTA·2Na (Aldrich, Milwaukee, Wis.)solution to the plasma. Dithiothreitol (DTT) was not included becauseAZA is immediately converted to 6MP in the presence of DTT. Thecartridges were rinsed with 2 ml of 0.2% acetic acid and thencentrifuged at 3200 rpm for 5 minutes to remove excess water. Thesamples were eluted from the cartridges with 2 ml of methanol andevaporated to dryness under a stream of nitrogen at 37° C. Samples werethen reconstituted in 200 uL of mobile phase, vortexed for 30 seconds,transferred to 1.5 ml conical microfuge tubes and centrifuged in amicrocentrifuge for 5 minutes. A portion (0.175 ml) of supernatant wastransferred to HPLC vials.

6MP levels were then determined by HPLC. The analytical column was aHewlett-Packard (Rockville, Maryland) octadecylsilane (ODS) Hypersil,200×4.6 mm, 5 μm particle size. It was protected by a Zorbax (Mac-modAnalytical, Chadds Ford, Pennsylvania) ODS 4×12.5 mm guard column. Themobile phase was 0.8% acetonitrile in 1 mM triethylamine, adjusted to pH3.2 with phosphoric acid. Absorbance was monitored at 340 nm. Theinjection volume was 80 uL. Unknowns were determined by comparing themto a standard curve constructed the same day by adding known quantitiesof 6MP to blank plasma. The lower limit of quantification of 6MP was 2ng/ml. The mean calculated concentration ±coefficient of variation forthe 2 ng/ml and 50 ng/ml standards were 2.0 ng/ml ±18% and 50.2ng/ml±3.4%, respectively.

D. Study Medications: 1) Intravenous AZA, lyophilized as the sodium salt(Burroughs Wellcome, Research Triangle Park, N.C.). 2) Standard 50 mgoral tablet (Burroughs Wellcome, Research Triangle Park, N.C.). 3)Delayed-release 50 mg oral tablet (DRO). 4) Hydrophobic rectal form(HBF). Administered rectally via a pressurized foam canister. 50 mg ofAZA (Fermion/Orion Corporation, Espoo, Finland) is dissolved in a doseof foam containing witepsol H15 (an oleagenous base) to make ithydrophobic. 5) Hydrophilic rectal foam. Administered rectally via apressurized foam canister. 50 mg of AZA (Fermion/Orion Corporation,Espoo, Finland) is dissolved in a foam. The delayed-release oral andrectal foam forms of AZA were prepared by Tillotts Pharma A.G. (Ziefen,Switzerland).

E. Results:

1. Pharmacokinetic Parameters for IV Dosing:

The AUC, CL, V_(ds), and T_(½) (mean±SD) for all 24 subjects following50 mg AZA administered intravenously are listed in Table 2.

TABLE 2 PHARMACOKINETIC PARAMETERS FOR 6MP FOLLOWING 50 MG OF AZAADMINISTERED INTRAVENOUSLY TO 24 HEALTHY VOLUNTEERS* AUC CL V_(ds)T_(1/2) (ng.hr/ml) (L/kg.hr) (L/kg) (hr) 100.7 ± 30.5 3.8 ± 1.2 6.7 ±3.1 1.2 ± 0.37 *mean ± SD

2. Pharmacokinetic Parameters for Colonic Delivery:

The AUC, F, T_(MAX), and C_(MAX) (mean±SE) for each of the non-IVdelivery routes are listed in Table 3. The mean bioavailability of theoral preparation was significantly greater than for the otherpreparations, and the mean T_(MAX) of the DRO formulation wassignificantly greater than for the other formulations. None of the otherdifferences were statistically significant.

TABLE 3 PHARMACOKINETIC PARAMETERS FOR 6MP FOLLOWING 50 MG AZAADMINISTERED VIA ORAL, DRO, HBF AND HPF* Group AUC F T_(MAX) C_(MAX) (n= 6) (ng.hr/ml) (%) (hr) (ng/ml) Oral 55 ± 27 52 ± 26 1.8 ± 0.8 21 ± 13DRO 11 ± 9  13 ± 15 5.4 ± 0.2^(c) 5 ± 5^(c) HBF 5 ± 4 5 ± 4 2.1 ±0.3^(d) 2 ± 1^(d) HPF 3 ± 4 2 ± 3 2.0 ± 0.0^(e) 1 ± 1^(e) P value0.01^(a) 0.01^(a) 0.01^(b) 0.01^(a) ^(a)P values derived by analysis ofcovarience. Post-hoc tests (Duncan's): a-oral > DRO = HBF = HPF; b-DRO >oral = HBF = HPF. c-mean ± SE of the 5 subjects with detectableconcentrations of 6MP. d-mean ± SE of the 4 subjects with detectableconcentrations of 6MP. e-mean ± SE of the 3 subjects with detectableconcentrations of 6MP. *mean ± SE

3. Rectal Administration

The rectal foam preparations were well-tolerated. Twenty-two of thesubjects retained the foam for greater than 6 hours. One subjectreported expelling the hydrophobic foam after one hour and anotherreported expelling the hydrophobic foam after two hours. The subject whoreported expelling the foam after one hour did not have detectableabsorbtion. The subject who reported expelling the foam after 2 hourshad a C_(MAX) of 2.35 ng/ml at 3 hours. No adverse reactions to the foampreparations were reported.

F. Discussion: This example demonstrates that the systemicbioavailability of 6MP following dosing with delayed-release oral andrectal delivery formulations of AZA is significantly lower than thebioavailability of 6MP after standard oral AZA. There are severalpotential factors contributing to this observation. The most likely isthat the absorbtion of AZA across the colonic mucosa is reduced comparedto absorbtion across gastric and small intestinal mucosa due to absenceof specific transport mechanisms or differing rates of passiveabsorbtion. Reduced colonic absorbtion compared to jejunal absorbtionhas been demonstrated for 5-aminosalicylate (5-ASA) (S. Bondesen et al.,Br. J. Clin. Pharm., 25, 269 (1988)). AZA and 6MP may be more completelymetabolized in the colonic mucosa of the more proximal GI tract. Inaddition, some AZA may be lost in the stool. Fecal excretion of 5-ASAfollowing administration of Eudragit-coated tablets is approximately 25%(B. Norlander et al., Aliment. Pharmacol. Therap., 4, 497 (1990)).

Following absorbtion, AZA is quickly converted to 6MP in plasma. Thisconversion occurs as the result of non-enzymatic attack bysulffhydril-containing compounds such as glutathione on the bond betweenthe 6MP molecule and the imidazole ring of AZA (L. Lennard et al., Clin.Pharmacol. Ther., 46, 149 (1989)). Glutathione is present in everymammalian cell, including colonic epithelial cells and lymphocytes, andprior studies have shown that lymphocytes contain the enzymes necessaryto convert 6MP to the active metabolites, the 6TGNs (B. Bostrom et al.,Am. J. Ped. Hem./Onc., 15, 80 (1993)). It is, therefore, reasonable toexpect that topical delivery of AZA will result in localinmmunosuppressive effects on colonic lymphocytes.

This example demonstrates that colonic delivery of AZA results insignificantly less 6MP bioavailability that standard oral AZA. It isbelieved that colonic delivery of AZA can reduce the drug's toxicity byreducing systemic exposure to 6MP. In addition, this topical form of AZAadministration can allow delivery of higher, locally concentrated dosesto intraepithelial and lamina propria colonic lymphocytes.

EXAMPLE 5 Treatment of Patient at Risk for Colorectal Polyps

A patient is identified as being at risk for development of colorectaladenomas or cancer due to either prior history of colorectal adenomatouspolyps or the presence of other conditions associated with at-riskpatients. Delayed release of oral azathioprine is administered at a doseof 150-1000 mg/day to prevent the recurrence or primary development ofcolorectal adenomatous polyps. The delayed release azathioprine iswell-tolerated and results in minimal systemic absorption.

All publications and patents are incorporated by reference herein, asthough individually incorporated by reference. The invention has beendescribed with reference to various specific and preferred embodimentsand techniques. However, it should be understood that many variationsand modifications may be made while remaining within the spirit andscope of the invention.

What is claimed is:
 1. An enema formulation comprising an amount ofazathioprine effective to prevent colorectal adenomas withoutdose-limiting system toxicity, in combination with a flowable carrier,and having a core of azathioprine that is released in the lowerintestinal tract.
 2. An enema formulation comprising an amount ofazathioprine effective to prevent colorectal adenomas withoutdose-limiting system toxicity, in combination with a flowable carrier,and having enterically-coated microparticles of azathioprine that arereleased in the lower intestinal tract.
 3. An enterically-coated unitdosage form adapted for oral administration, comprising an amount ofazathioprine effective to prevent colorectal adenomas withoutdose-limiting system toxicity, wherein the azathioprine is released inthe terminal portion of the ileum and the colon.